Despite significant advancements in the treatment of autoimmunity, cancer and infectious diseases, major challenges in the global healthcare industry remain. These major challenges are due, in part, to the ability of cells to modulate the immune response via cell surface polypeptides. Through some cell surface polypeptides cells and microorganisms have usurped signaling pathways to attenuate the monitoring mechanisms of the host immune system and inhibit immune responses to them, which leads to the development of disease phenotypes. Still, development of in vivo systems to optimally determine the therapeutic potential of new targeted therapies for autoimmunity, cancer and infectious diseases that are designed to modulate the immune responses to such disease pathologies and determine the molecular aspects of how such cells manipulate immune responses is lacking. Such in viva systems provide a source for assays for assessing the therapeutic efficacy and development of candidate agents for the treatment of autoimmunity, cancer and infectious diseases in the future.